Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists

Abstract

The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.

Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome

“…Interestingly, Leap2 expression was significantly and positively correlated with the ileal mRNA levels of Ppara , Faah , and Gde1 , but not Abhd6 , and negatively with those of Plcb1 and Trpv2 , but not Cnr2 and Pparg ( Figure 7 ). These correlations might suggest the implication of the eCBome, and in particular, of NAEs—which are biosynthesized through GDE1 (among other enzymes) and (like N -acyl-glycines) are degraded by FAAH, and act as agonists at PPARα (as in the case of OEA and PEA, similar to N -acyl-glycines) and PPARγ (as in the case of AEA) and/or antagonists at TRPV2 (as in the case of OEA and N -linoleoyl-ethanolamine [LEA]) [ 7 , 24 , 25 ]—in Leap2 up-regulation during the development of HFHS-induced glucose intolerance and obesity. The negative correlation with Plcb1 might suggest instead the existence of a negative correlation with 2-MAGs, of whose biosynthesis this enzyme catalyzes the rate-limiting step.…”

Nonpungent N-AVAM Capsaicin Analogues and Cancer Therapy

“…35 Moriello et al (2018) used the HATU reagent to obtain N-AVAM capsaicin analogues. 36 The starting material for the synthesis was the relevant fatty acyl methyl esters. The fatty acyl methyl esters were hydrolyzed to yield the corresponding fatty acid, which was then reacted with 12 (in the presence of DIPEA in anhydrous DMF) using the azabezotriazole based coupling agent HATU to obtain robust yields of N-AVAM capsaicin analogues.…”

“…The fatty acyl methyl esters were hydrolyzed to yield the corresponding fatty acid, which was then reacted with 12 (in the presence of DIPEA in anhydrous DMF) using the azabezotriazole based coupling agent HATU to obtain robust yields of N-AVAM capsaicin analogues. 36 Scheme 12 shows the schema of this coupling reaction using oleic acid (23) as an example reactant for the reaction. The reaction of 23 with 4-hydroxy-3vanillylamine (in the presence of HATU) yields 5.…”

High‐resolution structures of transient receptor potential vanilloid channels: Unveiling a functionally diverse group of ion channels

“…Unfortunately, these compounds also activated TRPV1 and are thus still not specific. 66 Although these first explorative studies have shown the usefulness in drug design, the current structures are not of a high enough resolution to genuinely push this field forward.…”